A Panax quinquefolius-Based Preparation Prevents the Impact of 5-FU on Activity/Exploration Behaviors and Not on Cognitive Functions Mitigating Gut Microbiota and Inflammation in Mice

SIMPLE SUMMARY: Chemotherapy-related cognitive impairment (CRCI) and fatigue worsen the quality of life (QoL) of cancer patients. Multicenter studies have shown that Panax quinquefolius and vitamin C, respectively, were effective in reducing the symptoms of fatigue in treated cancer patients. We developed a behavioral C57Bl/6j mouse model to study the impact of 5-Fluorouracil (5-FU) chemotherapy on activity/fatigue, emotional reactivity and cognitive functions. We used this model to evaluate the potentially beneficial role of a Panax quinquefolius-based solution containing vitamin C (Qiseng(®)) or vitamin C alone in these chemotherapy side effects. We established that Qiseng(®) prevents the reduction in activity/exploration and symptoms of fatigue induced by 5-FU and dampens chemotherapy-induced intestinal dysbiosis and systemic inflammation. We further showed that Qiseng(®) decreases macrophage infiltration in the intestinal compartment, thus preventing, at least in part, the systemic elevation of IL-6 and MCP-1 and further reducing the neuroinflammation likely responsible for the fatigue induced by chemotherapy, a major advance toward improving the QoL of patients. ABSTRACT: Chemotherapy-related cognitive impairment (CRCI) and fatigue constitute common complaints among cancer patient survivors. Panax quinquefolius has been shown to be effective against fatigue in treated cancer patients. We developed a behavioral C57Bl/6j mouse model to study the role of a Panax quinquefolius-based solution containing vitamin C (Qiseng(®)) or vitamin C alone in activity/fatigue, emotional reactivity and cognitive functions impacted by 5-Fluorouracil (5-FU) chemotherapy. 5-FU significantly reduces the locomotor/exploration activity potentially associated with fatigue, evokes spatial cognitive impairments and leads to a decreased neurogenesis within the hippocampus (Hp). Qiseng(®) fully prevents the impact of chemotherapy on activity/fatigue and on neurogenesis, specifically in the ventral Hp. We observed that the chemotherapy treatment induces intestinal damage and inflammation associated with increased levels of Lactobacilli in mouse gut microbiota and increased expression of plasma pro-inflammatory cytokines, notably IL-6 and MCP-1. We demonstrated that Qiseng(®) prevents the 5-FU-induced increase in Lactobacilli levels and further compensates the 5-FU-induced cytokine release. Concomitantly, in the brains of 5-FU-treated mice, Qiseng(®) partially attenuates the IL-6 receptor gp130 expression associated with a decreased proliferation of neural stem cells in the Hp. In conclusion, Qiseng(®) prevents the symptoms of fatigue, reduced chemotherapy-induced neuroinflammation and altered neurogenesis, while regulating the mouse gut microbiota composition, thus protecting against intestinal and systemic inflammation.